Tumors, virus-infected cells, and diseased cells characteristically express atypical, potentially immunoreactive antigens. Accumulating evidence suggests that the failure of the immune system to mount an effective response against progressively growing tumors or virally infected cells is not due to a lack of recognizable antigens. Immunosuppression is poorly understood and mechanisms by which cells escape immune surveillance have been poorly explored. Recently, it has been shown that cytotoxic T cells become tolerized by a reduction in local concentrations of tryptophan that are elicited by indoleamine 2,3-dioxygenase-1 (IDO1) activity.
IDO1 is an oxidoreductase that catalyzes the rate-limiting step in tryptophan catabolism. This enzyme is structurally distinct from tryptophan dioxygenase (TDO), which is responsible for dietary tryptophan catabolism in the liver. IDO1 is an IFN-γ target gene that has been suggested to play a role in immunomodulation (Mellor and Munn (1999) Immunol. Today, 20:469-473). Elevation of IDO1 activity depletes the levels of tryptophan in local cellular environments. Induction of IDO1 in antigen-presenting cells, where IDO1 is regulated by IFN-γ, blocks the activation of T cells, which are especially sensitive to tryptophan depletion. T cells must undergo 1-2 rounds of cell division to become activated, but in response to tryptophan depletion they arrest in G1 instead. In this way, IDO1 has been proposed to inhibit the TH1 responses that promote cytotoxic T cell development.
IDO1 has been proposed to modulate gene expression. This modulation is proposed to occur through a pathway involving GCN2, whose activation has been shown to lead to altered gene expression. The proposed pathway involves the following steps. First, IDO1 activity results in the metabolism of tryptophan. Second, the deprivation of tryptophan leads to tRNAs being uncharged. The presence of uncharged tRNAs results in the activation of GCN2 kinase and a general response pathway for amino acid starvation. Third, the active GCN2 kinase phosphorylates serine 52 of the alpha subunit of eukaryotic initiation factor 2 (eIF2α), which is known to be an important translation control mechanism. The regulation of eIF2α activity is governed by the phosphorylation of serine 52. Currently, there are at least three known kinases, i.e., IFN-inducible dsRNA-dependent protein kinase, heme-regulated repressor, and general control (GCN2), which can phosphorylate serine 52 in eIF2α. The phosphorylation of serine 52 in eIF2α prevents the GDP-GTP exchange activity of eIF2α resulting in the suppression of protein synthesis.
GCN2 has been shown to be important for IDO1-dependent responses since a GCN2 knock-out animal phenocopies the IDO1 knock-out animal.
The role of IDO1 in immunosuppression has been demonstrated by the ability of 1-methyl-tryptophan (1MT), a specific and bioactive IDO1 inhibitor (Cady and Sono (1991) Arch. Biochem. Biophys. 291:326-333), to elicit MHC-restricted and T cell-mediated rejection of allogeneic mouse concepti (Mellor et al. (2001) Nat. Immunol. 2:64-68; Munn et al. (1998) Science. 281: 1191-93). This effect is consistent with the high levels of IDO1 expression in placental trophoblast cells (Sedlmayr et al. (2002) Mol. Hum. Reprod. 8:385-391).
Significantly, IDO1 activity has been shown to be elevated frequently in human tumors and/or in cancer patients (Yasui et al. (1986) Proc. Natl. Acad. Sci. USA. 83:6622-26; Taylor and Feng (1991) FASEB J. 5:2516-22). Since IDO1 can modulate immune responses, one logical implication is that IDO1 elevation in cancer may promote tumor immunosuppression (Mellor and Munn (1999) Immunol. Today, 20:469-473; Munn et al. (1999) J. Exp. Med. 189:1363-72; Munn et al. (1998) Science. 281:1191-93). This possibility is supported by the observation that many cancers, including breast cancer, are characterized by a loss of beneficial immune functions that can limit malignant development. For example, TH1 responses (of which IFN-γ production is a hallmark) that promote the production of cytotoxic T cells are suppressed during cancer progression. A resultant hypothesis from this data was that if IDO1 drives cancer progression by blunting T cell activation, then IDO1 inhibition in animals should blunt tumor growth by reversing IDO1-mediated immunosuppression.
Notably, there are two stereoisomers of the IDO1 inhibitor 1MT, e.g., D-1MT and L-1MT. L-1MT inhibits IDO1 and exhibits a characteristic pattern of antitumor activities. In contrast, D-1MT shares the same in vivo properties, but does not inhibit IDO1 itself. One explanation for these results is that D-LMT inhibits an enzyme that is related to, but distinct from IDO1. However, no enzymes related to IDO1 have been identified.